Brecanavir (BCV, GW640385) is a new protease inhibitor (PI) in phase 2b clinical development by GlaxoSmithKline (Glaxo). It has shown powerful antiviral activity against both wild-type and highly drug-resistant HIV. One of its main attributes is that it may be used at a relatively low dose, which could potentially translate into fewer and milder side effects.1

Much was learned about brecanavir in 2005 at the last Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) based on the results from two important studies. The first was an open-label, single-arm study in which 31 HIV-1-infected adults (naive and experienced) with CD4+ cell counts greater than 200 cells/mm3 and HIV-1 RNA levels above 1,000 copies/mL received brecanavir 300 mg twice daily + ritonavir (RTV, Norvir) 100 mg twice daily, in combination with two nucleoside reverse transcriptase inhibitors. The proportion of patients achieving HIV-1 RNA levels below 400 and 50 copies/mL were 81% and 77%, respectively, at week 24 based on an intent-to-treat, missing-or-discontinuation-equals-failure analysis.2 At that time, it was already known that brecanavir caused no unfavorable drug interactions when combined with zidovudine (AZT, Retrovir) or lamivudine (3TC, Epivir). Its interactions with tenofovir (TDF, Viread), however, were less certain.

The second ICAAC study described the pharmacokinetic interactions between brecanavir and tenofovir in healthy volunteers.3 When tenofovir 300 mg was coadministered with brecanavir 300 mg twice daily + ritonavir 100 mg twice daily, the regimen appeared to be well tolerated and increased tenofovir concentrations by 24% to 32%, brecanavir concentrations by 15% to 20%, and ritonavir concentrations by 31% to 39% for both area under the curve and maximum plasma concentrations. These increases in drug exposure are not thought to require changes in dosing, but monitoring for tenofovir-related side effects or toxicity might be warranted.

At the XVI International AIDS Conference, additional data were presented regarding drug interactions between brecanavir and other PIs. Brecanavir is a known substrate of CYP450 3A4, the most important cytochrome P450 isoenzyme involved in metabolizing PIs and non-nucleoside reverse transcriptase inhibitors. Thus, the bioavailability of brecanavir is significantly increased when boosted with ritonavir and when taken with meals. This finding has prompted the possibility of using brecanavir in combination with another PI in a double-boosted regimen.

Pharmacokinetic analysis of the brecanavir + tipranavir combination could not be completed since this arm was prematurely discontinued before steady-state conditions for tipranavir were reached. This decision was based on the observation of significant liver transaminase elevations associated with the use of this combination in seven of 12 individuals. As such, the brecanavir + tipranavir combination was felt to be poorly tolerated with a high probability of negative interactions.

Shelton et al concluded that brecanavir may be co-administered with lopinavir/ritonavir without dose adjustment. Since plasma exposure to both brecanavir and atazanavir increased when the two agents were co-administered, reducing the dose of atazanavir may be necessary. Brecanavir should not be co-administered with tipranavir due to reduced plasma brecanavir trough concentrations.

Based on the in vitro and in vivo data obtained for brecanavir thus far, it appears that this agent could be highly effective for treatment-experienced HIV patients. Given that dual ritonavir-boosted PIs are frequently used in this population, it is important that we understand the pharmacokinetic interactions when combining these different drugs. On the other hand, the recent approval of TMC114 (darunavir, Prezista), the availability of TMC125 (etravirine) under the Early Access Program, and progress in the development of other agents, such as maraviroc (UK-427,857; a CCR5 entry inhibitor) and the Merck & Co. 0518 integrase inhibitor, may preclude the pressing need for double-boosted PIs in the near future.

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